The present invention relates generally to processes for preparing 1,2,4-thiadiazoles, and more particularly to processes for preparing 5-phenyl-3-thioureido-1,2,4-thiadiazole.
5-phenyl-3-thioureido-1,2,4-thiadiazole (PTT) is used in the preparation of agricultural fungicides. Kurzer (J. Chem. Soc., Perkin Trans. (1985), 1(2), 311-314) discloses the synthesis of PTT from 3-[Nxe2x80x2-(benzoyl)thioureido]-5-phenyl-1,2,4-thiadiazole (BzPTT). The conversion is effected by treating the BzPTT with a boiling 3 M aqueous solution of NaOH for 6-8 minutes, followed by acidification of the reaction milieu with concentrated hydrochloric acid, and then basification with gaseous ammonia. The PTT is recrystallized in a solution of acetone/ethanol (1:1 v/v) (300 mL/g) or nitrobenzene (5 ml/g) to provide an overall 85% yield recovery, on a 10.2 g-scale reaction.
Kurzer (J. Heterocycl. Chem., (1989), 26, 355) discloses the synthesis of 5-Phenyl-3-thioureido-1,2,4-thiadiazole (PTT) from 1-ethoxycarbonyl-3,5-(3xe2x80x2-phenyl-1xe2x80x2,2xe2x80x2,4xe2x80x2-thiadiazol-3xe2x80x2-yl) thiourea (EtPTT). EtPTT is converted to PTT by suspending the EtPTT in a boiling solution of ethanol and NaOH (3 M) with reflux for 1 hour, acidifying the reaction milieu with 3 M hydrochloric acid, and recrystallizing the PTT from dimethylformamide (DMF). The PTT was isolated in 72% yield, on a 1.54 g-scale reaction.
The present invention provides a method by which PTT is prepared by deprotecting BzPTT with an aqueous solution of KOH, preferably 2-3 M KOH. It has been discovered that the use of KOH provides PTT in both higher yields and purity than that achieved using NaOH.
It has been unexpectedly found that the process of the present invention generally does not require chromatographic purification of the PTT and provides PTT containing less than 10% by wt., preferably less than 5% by wt., more preferably less than 2% by wt., and most preferably less than 1% by wt. of undesired by-products.
In one aspect, the present invention provides a method for the preparation of a compound of the Formula I 
comprising the step of: (a) treating a compound of the Formula II 
with KOH in the presence of a polar protic solvent, such as water or a combination of water and an organic solvent, at a temperature and for a time sufficient to form the compound of the Formula I.
Preferred embodiments of the method of the invention employ one or more of the following: (a) an aqueous solution as the polar protic solvent; (b) a reaction temperature of 50-60xc2x0 C.; (c) rapid addition of a KOH-containing solution to the reaction solution; (d) a reaction time of 30-60 min.; (e) a 2-3 M KOH aqueous solution; and (f) vigorous agitation of the reaction milieu.
According to other preferred embodiments, the process can further comprise one or more of the following steps: (a) acidifying the reaction milieu with an inorganic acid; (b) basifying the acidic reaction milieu with an amine, such as ammonia, a primary amine, a secondary amine, a tertiary amine or a heterocyclic amine; (c) salting-out the compound of the Formula I from the reaction milieu; (d) isolating the compound of the Formula I by separating the solid form of the compound from a supernatant, such as the reaction solution; (e) drying the compound of the Formula I; (f) adjusting the pH of the reaction milieu to solubilize the benzoic acid by-product and leave the compound of the Formula I as a particulate solid in solution; (g) washing the compound of the Formula I with an aqueous solution; and (h) crystallizing the compound of the Formula I.
Scheme I includes a comparison of the process of the prior art and that of the present invention. Although not shown in Scheme I, benzoic acid (BzOA) is a by-product of the reaction. The yields of the present process depend, among other things, upon the temperature at which the treatment is conducted and the equivalent ratio of the KOH to the compound of the Formula II.
The process of the present invention can be run at temperatures ranging from about 50xc2x0 C. to a temperature which is at or below the boiling point of the organic solvent(s) used. The optimal temperature for running the reaction will depend, among other things, upon the organic solvent or combination of organic solvents used to run the reaction. If the reaction solution is water, the optimal temperature will generally range from about 50-70xc2x0 C., preferably about 50-60xc2x0 C., more preferably about 60xc2x0 C. If the reaction solution comprises a combination of water and an organic solvent, the preferred reaction temperature is 60-65xc2x0 C.
The process of the invention can be run at ambient to elevated pressure or generally from about atmospheric pressure or 1 atmosphere to about 10 atmospheres. The preferred pressure range is atmospheric pressure.
The process of the invention will be run for a period of time sufficient to form the compound of the Formula I in the desired yield and purity. The reaction time can take 0.5-1.5 hours, typically 0.5-1 hours, for completion and can vary according to the reaction temperature, the reaction solution employed, the equivalent ratio of KOH to the compound of the Formula II, the composition of the reaction solvent, the efficiency of the agitation employed during the reaction, and other reasons.
The concentration of a compound of the Formula II in the reaction solution can range from about 5-10%, preferably 5-6.5% by wt. based upon the final weight of the reaction mixture. Generally, about 9-11.5 volumes (L) of reaction solution per Kg of the compound of the Formula II are used.
The molar ratio of KOH:compound of the Formula II will vary between about 1:1 to about 10:1, preferably about 8:1 to about 10:1, and is most preferably about 9:1.
The compound of the Formula I can be isolated from the reaction mixture and purified according to the methods disclosed in Example 1 or according to other methods known to those of skill in the art. A first method of isolating the compound of the Formula I includes the steps of: (a) acidifying the reaction milieu with an inorganic acid; (b) basifying the resulting acidic milieu with an amine; (c) separating the particulate compound of the Formula I from the reaction supernatant; and (d) drying the compound of the Formula I. This first method is particularly useful when the reaction milieu contains no added buffering agents.
A second method of isolating the compound of the Formula I includes the steps of: (a) cooling the initial alkaline solution to 0xc2x0 C.; (b) filtering the precipitated white product; (c) washing the solid with water and (d) drying. (See example 2.)
A third method of isolating the compound of the Formula I, preferably from a buffered reaction solution, includes the steps of: (a) acidifying the reaction milieu with an inorganic acid to a pH more than about 0.5 pH units greater than the pKa of benzoic acid; (b) separating the particulate compound of the Formula I from the reaction supernatant; and (c) drying the compound of the Formula I.
A fourth method of isolating the compound of the Formula I, preferably from an unbuffered reaction solution, includes the steps of: (a) acidifying the reaction milieu with an acidic buffered solution to a pH of about 0.5 pH units or greater than the pKa of benzoic acid; (b) separating the particulate compound of the Formula I from the reaction supernatant; and (c) drying the compound of the Formula I.
The solubility of the BzOA in the reaction solution is adjusted by controlling the pH and/or composition of the reaction solution. Generally, BzOA is completely soluble at concentrations below its saturation point in solutions having a pH about 1 pH unit greater than the pKa of BzOA. In its protonated form, BzOA can be solubilized in the reaction medium by increasing the concentration of organic solvent in the medium.
The method of the invention can be conducted in water, a biphasic reaction solution or a mixture of water and an organic solvent. A wide range of organic solvents can be employed in the presently claimed process. The organic solvent will generally be able to dissolve at least a portion of either one or both of the compound of the Formula I and the KOH. The solubility of the compounds of the Formulae I and/or II in the reaction solution may be very low. By proper design of the reaction solution, the solubility of these compounds may be adjusted to favor product formation or enhance product purity. For example, a reaction solvent which preferentially dissolves the compound of the Formula II over the compound of the Formula I will generally improve the yield and purity of the compound of the Formula I. The organic solvents that may be useful in the present invention include, but are not limited to, mixtures of water with water-miscible organic solvents.
Suitable polar solvents include dimethoxymethane, dimethoxyethane, tetrahydrofuran (THF), 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl ethyl ether, and t-butyl methyl ether.
Suitable protic solvents may include, by way of example and without limitation, water, ethylene glycol, diethylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, glycerol, methanol, ethanol, 1-propanol and 2-propanol.
Suitable aprotic solvents may include, by way of example and without limitation, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), acetonitrile, dimethyl sulfoxide, propionitrile, ethyl methyl ketone, sulfolane, and tetramethylurea.
Suitable amines which can be used to basify the reaction milieu once it has been acidified include ammonia, ammonium hydroxide, primary amine, secondary amine, tertiary amine, aliphatic amine and aromatic amine. Exemplary amines include, but are not limited to, pyridine, aniline, benzylamine, n-butylamine, cyclohexylamine, diethylamine, diisopropylamine, dimethylamine, diphenylamine, ethylamine, ethylenediamine, hexamethylenediamine, morpholine, piperazine, piperidine, pyrrolidine, m-toluidine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylarnine, N,N-dimethylcyclohexylamine, N,N,Nxe2x80x2-triethylenediamine, tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.
The acidic agent used to acidify the reaction milieu upon completion of the debenzoylation includes inorganic acids such as HCl, H2SO4, H2SO3, H3PO4, H3PO3, HNO3, HF, HBr, HI, combinations thereof and acidic salts thereof; and organic acids such as trifluoroacetic acid (TFA), chloroacetic acid, alkyl sulfonic acids, ethanesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, p-toluenesulfonic acid and combinations thereof.
Any known method of separating a solid from a liquid can be used in the present invention to separate the precipitated compound of the Formula I from a supernatant. Exemplary methods include filtration, centrifugation, decantation, settling of solids, and combinations thereof.
The compound of the Formula I can be dried using any known method of drying solids. If heat is employed during the drying process, it is preferred that the temperature of the compound of the Formula I not exceed its melting point. Exemplary methods of drying solids include air drying, oven drying, vacuum oven drying, tray drying, tumble drying, paddle drying freeze drying, heated drying, ambient temperature drying, and combinations thereof.
The compound of the Formula II was prepared according to Kurzer (J. Chem. Soc., Perkin Trans. (1985), 1(2), 311-314), the disclosure of which is hereby incorporated by reference in its entirety. Unless otherwise noted, all other materials used herein are commercially available from sources such as Aldrich Chemical Co., Inc., Aceto Corporation, Acros Organics, Air Products, Apollo Scientific, Ltd., Albright and Wilson Americas, Bachem, AlliedSignal Corporation, BASF Aktiengesellschaft, Borregaard Fine Chemicals, Bridgewater Chemical, BNFL Fluorochemicals Ltd., Eastman Chemical Company, Elan Incorporated, Fluorochem Ltd., Fluka Chemie AG, Fisher Scientific, INDOFINE Chemical Company, Inc., JRD Fluorochemicals Ltd., Kanto Chemicals Co., Inc., Lancaster Synthesis Ltd., Research Organics Inc., Strem Chemicals, Inc., Wychem Ltd., or VWR Scientific.
The foregoing will be better understood with reference to the following examples which detail certain procedures for the manufacture of 1,2,4-thiadiazoles according to the present invention. All references made to these examples are for the purposes of illustration. They are not to be considered limiting as to the scope and nature of the present invention since further modifications of the disclosed invention will be apparent to those skilled in the art. All such modifications are deemed to be within the scope of the present invention.